Alzheimer's disease develops as the result of a complex series of steps that ultimately lead to neuronal cell death and the loss of cognitive function. At present, two steps appear to be of particular importance. The first is a synthesis of the amyloid precursor protein (APP) and its processing into the Aβ peptides, which then polymerize and deposit as the amyloid filaments that are the hallmark of Alzheimer's disease (Selkoe, J. Biol. Chem. 271:18295 (1996); Scheuner; et al., Nature Med. 2:864 (1996); Goate, et al., Nature 349:704 (1991)). Coupled to this process is a special form of inflammation and acute phase response in the brain that leads to an increase in the production of amyloid-associated proteins, α1-antichymotrypsin (ACT) and complement activation (Abraham, et al., Cell 52:487 (1989)). In vitro studies have shown that ACT and another amyloid-associated protein, apolipoprotein-E (ApoE), regulate the polymerization of Aβ peptides into amyloid filaments (Yee, et al., Nature 372:92 (1994)). The ApoE 4 and, possibly, the ACT-A alleles are inherited risk factors for Alzheimer's disease (Corder, et al., Science 261:921 (1992)).
Several facts suggest a direct connection between increased APP levels and the development of Alzheimer's disease and further suggest that such an increase may be linked to inflammatory mechanisms:                a) Down syndrome brains in trisomy-16 mice show increased APP protein levels beyond the 0.5-fold increase that would be expected by gene dosage (Neve, et al., Mol. Brain Res. 39:185 (1996)).        b) Over-expression of APP protein in transgenic mice is necessary, even in the presence of FAD mutations, for sufficient Aβ peptide production to lead to the development of amyloid filament deposits and an Alzheimer's-like pathology (Quon, et al., Nature 352:239 (1991)). Furthermore, APP protein synthesis correlates with Aβ peptide production both in vitro and in vivo (Ho, et al., J. Biol. Chem. 271:30929 (1996)).        c) Traumatic brain injury, a known risk factor for Alzheimer's disease, increases IL-1 as well as APP-immunoreactivity in rat brain (Nieto-Sampedro, et al., J. Neurosci. Res. 17:214 (1987)).        d) IL-1 injected into the rat cerebral cortex increases the steady-state levels of APP protein at the site of the lesion (Sheng, et al., Neurobiol. Aging 17:761 (1996)) and primary astrocytes have been shown to be a source of secreted Aβ peptides (Busciglio, et al., Proc. Natl. Acad. Sci. U.S.A. 90:2092 (1993)).        
The identification of the mechanisms by which inflammation leads to the overproduction of APP in brain cells may lead to new therapies for controlling Alzheimer's disease. Beyond this, the discovery of new methods and elements for regulating gene expression will provide new opportunities for controlling the production of recombinant genes both in vitro and in vivo.